3beta-cyclopentyl-androstane and pregnane derivatives



United States Patent The present invention relates to novel cyclopentano- 'phenanthrene compounds and to a process for the production thereof.

More particularly the present invention relates to novel 3-cyclopentadienyl and 3B-cyclopentyl-androstane and pregnane derivatives.

The novel compounds of the present invention are represented by the following formulas:

r O=O I15 3 l D In the above formulas Y represents a double bond or a saturated linkage between C-4 and C-5; Z represents a double bond or a saturated linkage between C-6 and C-7; R represents hydrogen or methyl; R represents hydrogen or a hydrocarbon carboxylic acyl group of less than 12 carbon atoms; R represents hydrogen or a lower alkyl group and R represents hydrogen or the group --OR wherein R represents hydrogen or a hydrocarbon carboxylic acyl group of less than 12 carbon atoms.

The acyl group is derived from hydrocarbon carboxylic acids containing less than 12 carbon atoms which may be saturated or unsaturated, .of straight, branched, cyclic or cyclic-aliphatic chain, aromatic and may be substituted by functional groups such as hydroxy, alkoxy containing up to 5 carbon atoms, acyloxy containing up to 12 carbon atoms, nitro, amino or halogen. Typical ester groups are the acetate, propionate, enanthate, benzoate, trimethylacetate, t-butylacetate, phenoxyacetate, cyclopentylpropionate, aminoacetate and ,B-chloropropiomate.

The compounds represented by Formulas A and C are androgenic type hormones possessing anabolic properties and anti-estrogenic activity. 7

The compounds represented by Formulas B and D are progestational agents exhibiting anti-ovulatory, antiandrogenic and anti-estrogenic activities.

The novel compounds of the present invention are prepared by the process illustrated by the following equation In the above formulas, E represents R R R R Y and Z have the same meaning as hereinabove set forth.

In practicing the process outlined above, the 3-ketoandrostane or pregnane derivative, or the corresponding 19-nor compound, is treated with cyclopentadiene in the presence of an alkali metal lower alkoxide, such as sodium ethoxide, for a period of time that may vary from 1 to 16 hours giving the corresponding 3-cyclopentanodienylidene derivative. Hydrogenation of this compound in the presence of a suitable catalyst such as platinum oxide affords the 3B-cyclopentyl derivative of the corresponding saturated androstane or pregnane or the respective l9-nor-compound.

The following specific examples serve to illustrate but are not intended to limit the scope of the present invention:

Example I To a solution of 0.30 g. of sodium in 20 cc. of ethanol was added rapidly a second solution of 2.9 g. of dihydroallotestosterone in 25 cc. of ethanol containing 6 cc. of freshly distilled cyclopentadiene. The mixture was kept at room temperature for one hour and then at 0 C. for an additional hour. The crystalline product thus formed was filtered 0E, washed with cold ethanol and dried in vacuo, thus furnishing 3-cyclopentadienyliden-androstan- 17B-ol. The product has a melting point of 87 .=C.; [0:1 +13.f2 (CHCl A 280 m log e=4.36.

Following the above technique was treated 19-nor-dihydroallotestosterone affording 3-cyclopentadienylidene-19- nor-androstan-17B-ol.

3 Example II A suspension of 2 g. of 3-cyclopentadienyliden-androstan-17fi-ol in 20 ml. of ethanol was shaken with 200 mg. of platinum oxide under an atmosphere of hydrogen until 3 molar equivalents of this gas were absorbed. Removal of the catalyst by filtration and evaporation to dryness of the filtrate gave a solid residue which upon crystallization from hexane afforded 3fl-cyclopentyl-androstan-17B- ol with a melting point of 11214 C.; [(11 +12 (CHCl Upon hydrogenation of 3-cyclopentadienylidene-l9- nor-androstan-l7fi-ol was obtained 3B-cyclopentyl-19-norandrostan-17B-ol.

Example III A solution of 3 g. of 17a.-methyl-androstan-17 6-01-3- one and 6 cc. of freshly distilled cyclopentadiene in 35 ml. of ethanol was added to a solution of 480 mg. of sodium in 20 cc. of ethanol. After 16 hours at room temperature, the mixture was poured into cold water, the formed precipitate was filtered off, washed with water and dried in vacuo. Recrystallization from ethanol atforded 3-cyclopentadienylidene 17a methyl-androstan- 1718-01 with a melting point of 155-57 0.; [a1 7.4 (CHCl A 280 my, log =4.36.

17a-methyl-19-nor-androstan-l7fi-ol-3-one was treated exactly by the above technique giving 3-cyclopentadienylidene-l7a-methyl-l9-nor-androstan-17 8-01.

Example IV Example V 3 g. of testosterone were treated following the procedure described in Example III, furnishing 3-cyclopentadienyliden-A -androsten-17 8-01 with a melting point of l90-l94 C.; [04 +331.6 (CHCl A 328-30 m log E=4.54.

l9-nor-testosterone was treated by the same technique giving 3-cyclopentadienylidene 19 nor M-androsten- Example VI 3 g. of progesterone were treated in accordance with Example III, affording 3-cyclopentadienylidene M-pregnene-20-one, with a melting point of 16062 C.; [ab +428 (CHCl A 328-330 my, log E=4.52-

Upon treatment of 19-nor-progester0ne by the same technique there was obtained 3-cyclopentadienylidene-l9- nor-A -pregnen-20one.

Example VII 2 g. of 3-cyclopentadienylidene-A -pregnen-20-one was Example VIII 3 g. of 6-dehydro-l7a-hydroxy-progesterone (obtained by chloranil dehydrogenation of 17a-hydroxy-progesterone) was treated following the technique described in Example III affording 3-cyclopentadienyliden-l7a-hydroxy-A -pregnadien-ZO-one with a melting point of 21012 C.; [11.1 +'193 (CHCl A 364 my, log =4.67.

6-dehydro-17a-hydroxy-l9 nor-progesterone obtained by chloranil dehydrogenation of 17a-hydroxy-l9-nor-progesterone, was treated by the same method furnishing 3-cyclopentadienylidene 17oz hydroxy 19 nor A pregnadien-ZO-one.

Example IX Following the technique described in Example H (except that 5 molar equivalents of hydrogen were allowed to be absorbed by the compounds) there were hydrogenated 3 cyclopentadienylidene 17a hydroxy-M -pregnadien-20-one and 3-cyclopentadienylidene-l7a-hydroxy- 19-nor-A -pregnadien-ZO-one afiording correspondingly 3,8 cyclopentyl 17a hydroxy-allopregnan-ZO-one and Zip-cyclopentyl-l7arhydroxy-19-nor-allopregnan-20-one.

Example X 1 g. of 3cyclopentadienyliden-androstan-l713-01 in 10 cc. of pyridine was treated with acetic anhydride. The mixture was kept overnight at room temperature, then poured into cold water. The formed precipitate was filtered olf, washed with water and dried in vacuo.

Recrystallization from acetone-hexane afforded the 17- acetate of 3-cyclopentadienyliden-androstan-17,8-01.

Following the same technique, there were treated the compounds listed hereinafter with the indicated agent affording the corresponding products named below:

Starting compound Acylatlni agent Product 3-cyclopentadicnyll- Propionlc anhy- 17-proplonate of 3-cycloden-androstan-Ufldride. pen tadienylidenanol. drostan-17fl-ol. 3-cyclopentadienylr- Caproic anhydride-. 17-caproateof 3 cyclodene-l nor-andropentadienylidcne-l start-17501. nor-androstandmcl.

Do Cyclopentyl-pro- 17-cyclopentylproplonate plonic anhydride. o1 3-cyclopentadienylidcne-IQ-nor-androstan- 1718-01. 3&cyclopenty1-andro- Benzoylchloride... 17-benzoateof3 3cyclostan-17fi-ol. plentyl-androstan-flfio Do Propionic anhy- 17-propionute oi3fi-cyclodride. p]eutyl-androstan-17B- o 3B-cyclopentyl-19-nor- Oaprolc anhydride. l7-capr0ate of 3fl-cycloandrostan-17Bol. pentyl-19-nor-andro- I Stan-17601. D0 Acetic anhydride.... 17-acetate of zip-cyclopentyl-lQ-nor-androstan-17B-ol. 3-cyclopentadlenyll- Cyclopentyl-pro- I'I-cyclopentylproplouate denA androstcnpionic anhydride. of 3-cyclopentadicnyli- 1719c]. den-N-androsten- D0 Bcnzoyl chl0r1 le- 17-benzoateof3-cyclopentadienylidemmandrostcn-Hfi-ol. s-cyclopentadienyll- Caprolc anhydride. 17-caproate of 3-cyclodene-l -nor-A -anpentadienylidcnc-lfildrosten-HB-ol. nlor-A androstcn-flfl- D0 Benzoyl chloride 17-benzoate of 3-cyclopentadienylidene-wnlor-A -andr0sben-17flo Example XI A solution of 1 g. of 3-cyclopentadienylidene-17amethyl-androstan-17fi-ol, l g. of p-toluenesulfonic acid monohydrate, 50 cc. of acetic acid and 10 cc. of acetic anhydride after one hour reaction at room temperature was poured into water and stirred until the excess anhydride had hydrolyzed. Isolation of the product by ethyl acetate extraction and crystallization of the residue from acetone-ether gave the 17-acetate of 3-cyclopentadienyliden-17a-methyl-androstan-1713-01.

Following the same technique there were treated the compounds listed below with the indicated anhydride affording the corresponding products hereinafter set forth.

acacia Starting compound Acylating agent Product 3-eyc1opcntadienyli- Propionic anhy- 17-propl0nate of 3-cyc1odene-17a-methy1- dride. pentadienylidene-lhandrostan-Ufl-ol. methyl-androstan-Hfi- 3-cyclopentadienyl1- Oaproic anhydride. 17-caproate of 3-cyc1odene-lM-methylpentadienylidene-lh- 19-nor-nndrostanmethyl-IQ-nor-andro- 175-01. stan-17B-o1.

Do Oyclopentylpro- 17-cyc1opentylpropionate picnic anhydride. of 3-cyclopentadieny1idene-17a-methy1-19- nor-androstan-HB-ol. 3-cyc1opentadieny1l- Acetic anhydr1de l7-acetate of 3-cyc1opentdene-lh-hydroxyadienyIidene-Ua-hy- A pregnen-20one. droxy-A -pregnen-20- one. Do Propionlc anhy- 17-propionate of 3-cycl0- dride. pentadienylidene-lhhydrosy-A -pregnen- 20-one. 3B-cyc1opentyl-17a- Oaproic anhydr1de. 17-caproate of 3fl-cyc1omethyl-androstanpentyl-lh-methyl- 175-01. androstan-Ufi-ol.

Do Cyclopentylpro- 17-cyc1opentylprop1ouate pionic anhydride. of 3-cyc1openty1-17anllethyl-androstan-flflo 3,8-cyelopentyl-17a- Acetic anhydride. 17-acetate of SB-cyclomethy1-19-nor-anpentyl-17a-methyL19- drostan-17B-ol. nor-androstan-UB-ol.

Do Cyclopentyl-pro- 17-cyclopenty1propionate pionic anhydride. of 3fl-cyc1opentyl-17amethyl-IQ-nor-androstan-17fi-ol. 3fl-cyclopenty1-17- Caprolc anhydride... l7-caproate of 3fl-cyclohydroxy-allopregpentyl-lh-hydroxynan-ZO-one. a11opregnan-20-one.

Do Propionic anhy- 17-propionate of 3fi-cyc1odride. pentyl-lh-hydroxyallopreg'nan-20-one. 3fl-cycIopenty1-17a- Acetic anhydride. 17-acetate of 3fi-cyc1ohydroxy-lQ-norpentyl-lh-hydroxyallopregnan-20one. 19-nor-a1lopregnan-20- one. Do Cyclopentyl-pro- 17-cyc1openty1propionate pionic anhydride. of 3fl-eyclopentyl-17ahydroxy-lQ-nor-allopregnan-ZO-one.

I cla1m:

1. A compound of the following formula:

wherein Y is selected from the group consisting of a.

double bond and a saturated linkage between 0-4 and C-5; R is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms and-R is selected from the group consisting of hydrogen and lower alkyl.

2. 3-cyc1opentadienyliden-androstan-173-01.

3. 3-cyclopentadienylidene-19-nor-androstan-17B-ol.

4. 3-cyclopentadieny1idene 17a methyl androstan- 175-01.

5. 3 cyclopentadienyliden 17a methyl 19 norandrostan-17fi-ol.

6. 3-cyclopentadienyliden-A -androsten-175-01.

7. 3 cyclopentadienylidene 19 nor A -androsten- 175-01.

8. The 17-acetate of 3-cyclopentadienyliden-androstan- 175-01.

9. A compound of the following formula:

wherein R is selected from the group consisting of hydrogen and methyl; R is selected from the group consisting of hydrogen and a hydrocarbon carboxylic acyl group of less than 12 carbon atoms and R is selected from the group consisting of hydrogen and lower alkyl.

10. 3-cyc1opentyl-androstan-175-01.

11. 3-cyclopentyl-17u-methyl-l9-nor-androstan-17 8-01.

12. The 17-propionate of 3-cyclopentyl-androstan-175- 01.

13. A compound of the following formula:

wherein Z is selected from the group consisting of a double bond and a saturated linkage between C-6 and C-7; R is selected from the group consisting of hydrogen and methyl and R is selected from the group consisting of hydrogen, hydroxy and hydrocarbon carboxylic acyloxy of less than 12 carbon atoms.

14. 3-cyclopentadienylidene-M-pregnen-ZO-one.

15. 3-cyc1opentadienylidene-19-nor-A -pregnen-20-one.

16. 3 cyclopentadienylidene-l7a-hydroxy-A pregnen- 20-one.

17. 3 cy'clopentadienyilidene 17 a-hydroxy-19-nor-A pregnen-ZO-one.

18. The 17-acetate of 3cyclopentadienyl-idene-17a-hydroxy-M-pregnen-ZO-one.

19. A compound of the following formula:

Fig.

No references cited. 

9. A COMPOUND OF THE FOLLOWING FORMULA:
 19. A COMPOUND OF THE FOLLOWING FORMULA: 